4-methyl-16beta-mercapto-1,3,5(10)-estratrien-17beta-ol and its acylate



United States Patent C) 3,227,7334-METHYL-16fl-MERCAPTO-1,3,5(10)-ES'IRATRIEN- 17B-0L AND ITS ACYLATE Norio Tokutake, Ashiya-shi, Japan, assignor to Shionogi & (10., Ltd.,Osaka, Japan N Drawing. Filed Feb. 13, 1964, Ser. No. 344,528 Claimspriority, application Japan, Feb. 19, 1963, 38/ 8,831 6 Claims. (Cl.260-397.3)

The present invention relates to 4-methyl-l6 3-rnercapto-1,3,5(10)-estratrien-17,8-ol and its acylate. More particularly, itrelates to 4-methyl-16B-mercapto-1,3,5(l0)- estratrien-17 6-o1 and itsacylate represented by the formula:

wherein R and R each represents a hydrogen atom or a lower alkanoylgroup (e.g. acetyl, propionyl, butyryl).

The said 4 methyl l6 3-mercapto-1,3,5(10)-estratien- 175-01 and itsacylate of Formula I are useful as antiuterotropic agents.

Accordingly, it is a basic object of the present invention to embody4-methyl-l6,8-mercapto-1,3,5'(l0)-estratrien-l7 6-ol and its acylate ofFormula I. Another object of the invention is to embody4-methyl-16B-mercapto- 1,3,5(10)-estratrien-17 8-ol and its acylatehaving antiuterotropic activity. A further object of the invention is toembody a route for the synthesis of4-methyl-l6B-mercapto-1,3,5(l0)estratrien-l7fi-ol and its acylate. Theseand other objects will be apparent to those conversant with the art towhich the present invention pertains from the subsequent description.

The objective 4 methyl-16,8-mercapto-1,3,S(10)-estratrien-l7 3-ol andits acylate of Formula I are prepared from4-methyl-l,3,5(l0)-estratrien-17-one according to the following scheme:

O O H II th (OW 031. 0

ICC

I CH3 wherein R" and R' each represents a lower alkanoyl group (e.g.acetyl, propionyl, butyryl).

The starting material, 4-methyl-1,3,5(10)-estratrien-l7- one of FormulaII, is known [Caspi et al.: J. Chem. Soc., p. 1710 (1962)].

According to the present invention, the starting 17- ketone (II) isfirst subjected to enolesterification. The enolesterification may becarried out by treating the 17- ketone (II) with isopropenyl acetate inthe presence of sulfuric acid while refluxing. The resulting enolacetate (III) is then subjected to bromination. The bromination may beexecuted by treating the enol acetate (III) with bromine in an inertorganic solvent (e.g. carbon tetrachloride, chloroform, carbondisulfide) at a low temperature around 0 C. Then, the resultantl6a-bromo-17- ketone (IV) is subjected to reaction with thioalkanoicacid (e.g. thioacetic acid, thiopropionic acid, thiobutyric acid). Thereaction is usually effected by treating the 16oc-b10ll10- 17-ketone(IV) with an alkali metal salt of the thioalkanoic acid (e.g. sodiumthioacetate, potassium thioacetate, potassium thiopropionate, potassiumthiobutyrate) in an inert organic solvent (e.g. acetone, ether, dioxane,tetrahydrofuran) at room temperature 10 to 30 C.). The resultant 168-alkanoylthio-17-ketone (V) is then subjected to reduction. Thereduction may be carried out by treating thelfifl-alkanoylthio-l7-ket0ne (V) with an alkali metal hydride (e.g.lithium aluminum hydride, lithium borohydride, sodium borohydride) in aninert organic solvent (e.g. ether, dioxane, tetrahydrofuran, benzene),if necessary, while heating.

The thus-prepared 4-methyl-l6 3-mercapto 1,3,5 (10)- estratrien-17 8-olof Formula Ia may be further subjected to acylation. The acylation canbe effected by treating the 16fl-mercapto-17B-ol (Ia) with an alkanoicanhydride (e.g. acetic anhydride, propionic anhydride, butyricanhydride) in the presence of an organic base (e.g. pyridine, picoline,triethylamine) at a temperature from room temperature 10 to 30 C.) torefluxing temperature.

The thus-obtained 4-methy1-16/3-mercapto 1,3,5 (10)- estratrien-17B-olof Formula Ia and 4-methyl-16 3-a1kanoylthio-l7 3-alkanoyloxy-1,3,5( 10)estratriene of Formula Ib are useful as anti-uterotropic agents. Forinstance, 4-rnethy1-16f3-acetylthio-17,8-acetyloxy 1,3,5 (10)estratriene produced inhibition of uterine growth induced by 0.03microgram of estradiol, when subcutaneously administered to mice at adose of 0.3 milligram.

The following examples set forth illustratively presentlypreferredembodiments of the present invention. In the examples, the abbreviationshave following significances: g., gram(s); ml., millilitre(s); Anal.calcd., analysis calculated; and C., degrees centigrade. Other abbreviations have conventional significances.

3 Example 1 O O C CH3 6Q W l C H: CH3

Preparation of 4-methyl-17-acetyloxy 1,3,5(),16- estratetraene: Amixture of 4-methyl-1,3,5(10)-estratrien- 17-one (3.04 g.) andisopropenyl acetate (25 ml.) is combined together with a mixture ofcone. sulfuric acid (0.3 ml.) and isopropenyl acetate (1.5 ml.), and theresultant mixture is refluxed for 1 hour and then concentrated to a halfvolume in 30 minutes. The reaction mixture is cooled and shaken withether. The ether layer is separated, washed with dilute sodiumbicarbonate solution and water in order, dried over anhydrous sodiumsulfate and the solvent evaporated. The residue is chromatographed onalumina (25 g.) and eluted with petroleum ether. The eluate iscrystallized from a mixture of methanol and acetone (9:1) to give4-methyl-17-acetyloxy-1,3,5(10),16- estratetraene (2.35 g.) as crystalsmelting at 113 to 114 C., +819 (c.=1.046, chloroform).

Analysis.Calcd. for C H O C, 81.25; H, 8.44.

Found: C, 81.13; H, 8.35.

Example 2 O COCH:

Preparation of 4-methyl-16a-bromo-1,3,5(10) estratrien-17-one: Into asolution of 4-methyl-17-acetyloxy-1,3, 5 (10),16-estratetraene (2.30 g.)in carbon tetrachloride (45 ml.), there is suspended potassium carbonate(1.8 g.). A solution of bromine in carbon tetrachloride (129 mg./ ml.)is dropwise added to the suspension at a temperature not higher than 0C. while stirring until the colour of bromine is not decolorized. Theresultant mixture is combined with dilute sodium bisulfite solution fordecomposing excess of the bromine and shaken with chloroform. Thechloroform layer is separated, washed with water, dried over anhydroussodium sulfate and the solvent evaporated. The residue is crystallizedfrom methanol to give 4 methyl-16a-bromo-l,3,5(10)-estratrien-17-one(2.25 g.) as crystals melting at 163 to 164.5 C., [a] +1240 (c.=1.103,chloroform).

Analysis.Calcd. for C H OBr: C, 65.71; H, 6.68; Br, 23.01. Found: C,65.87; H, 6.70; Br, 23.18.

CH3 CH3 Preparation of4-methyl-16;3-acetylthio-1,3,5(10)-estratrien-17-one: To a solution of4-methy1-16a-brorno-1,3, 5(10)-estratrien-l7-one (1.99 g.) in anhydrousacetone (70 ml.), there is added potassium thioacetate (1.2 g.),

and the resultant mixture is stirred for 3.5 hours at room temperature(10 to 30 C.). The reaction mixture is combined with water (250 ml.).The separated substance is collected by filtration and crystallized fromacetone to give 4-methyl-16Bacetylthio-1,3,5(10)-estratrien 17- one(1.63 g.) as crystals melting at 211 to 213 C., [M +134.4 (c.=1.096,chloroform).

Analysis.Calcd. for C H O S: C, 73.64; H, 7.65; S,

9.36. Found: C, 73.69; H, 7.72; S, 9.40.

Example 4 Tsrr @3 CH3 CH3 Preparation of4-methy1-l6fi-mercapto-l,3,5(10)-estratrien-17B-ol: A solution of4-methyl-16B-acetylthio-l,3, 5(10)-estratrien-17-one (1.82 g.) inanhydrous tetrahydrofuran ml.) is dropwise added to a suspension oflithium aluminum hydride (1.1 g.) in anhydrous ether (100 ml.), and theresultant mixture is refluxed for 3.5 hours. The reaction mixture iscombined with a mixture of ice and water. The organic solvent layer isseparated, washed with 10% hydrochloric acid, water, 10% sodiumcarbonate solution and water in order, dried over anhydrous sodiumsulfate and the solvent evaporated. The residue is crystallized frommethanol to give 4-rnethyl-16fimercapto-1,3,5(10)-estratrien-l75-ol(1.44 g.) as crystals melting at 131 to 132 C.

Example 5 Y od r CH3 CH2 Preparation of 4-methyl-16fi-acetylthio-17Bacetyloxy- 1,3,5 10)-estratriene: 4-methyl-16fi-mercapto 1,3,5(10)-estratrien-17B-ol (1.40 g.) is combined with pyridine (30 ml.) andacetic anhydride (15 ml.), and the resultant mixture is heated on awater bath for 2.5 hours. After cooling, water is added thereto. Theprecipitate is collected by filtration, washed with water andcrystallized from acetone to give4-methyl-16,6-acetylthio-17fi-acetyloxy-1,3,5 (10)-estratriene (1.38 g.)as crystals melting at 178.5 to C., [a] +78.9 (c. -O.778, chlorofrom).

Analysis.Calcd. for C H O S: C, 71.46; H, 7.82; S, 8.30. Found: C,71.70; H, 7.84; S, 8.61.

What is claimed is: 1.4-methyl-16,8-mercapto-1,3,5(10)-estratrien-17fi-ol.

( IQaCOCH.

OCOCH:

]so 0 on.

2. 4-methyl-16fi-lower alkanoylthio-17fl-loweralkanoyloxy-1,3,5(10)-estratriene.

References Cited by the Examiner UNITED STATES PATENTS 2,928,847 3/1960Johns 260396.3

LEWIS GOTTS, Primary Examiner.

1. 4-METHYL-16B-MERCAPTO-1,3,5(10)-ESTRATRIEN-17B-OL. 4.4-METHYL-16B-LOWER ALKANOYLTHIO - 1,3,5(10) - ESTRATRIEN-17-ONE.